Process for producing 5-iodo-deoxy-uridine

ABSTRACT

Process for preparing 5-iodo-deoxy-uridine by treating 2&#39;&#39;-deoxyuridine with iodine and a cation exchange resin.

United States Patent Kiyanagi et a1.

3,852,266 Dec. 3, 1974 PROCESS FOR PRODUCING S-IODO-DEOXY-URIDINEInventors: Tetsuo Kiyanagi; Morio Suzuki;

Hiroshi Yoshino, all of Choshi, Japan Yamasa Shoyu Kabushiki Kaisha,Chiba-ken, Japan Filed: Dec. 22, 1971 Appl. No.: 211,098

Assignee:

Foreign Application Priority Data Dec. 24, 1970 Japan 45-116709 US. Cl260/2115 R Int. Cl C07d 51/52 Field of Search 260/211.5 R

OTHER PUBLICATIONS Chang et al., Biochemistry Pharmacology, Vol. 8, 11,1961, pp. 32-7 328.

Primary Examiner-Johnnie R. Brown Attorney, Agent, or FirmWenderoth,Lind & Ponack [57] ABSTRACT Process for preparing S-iodo-deoxy-uridineby treating 2-deoxy-uridine with iodine and a cation exchange resin.

5 Claims, N0 Drawings PROCESS FOR PRODUCING 5 -lODO-DEOXY-U RIDINE Thisinvention is concerned with improvement in the process for production ofS-iodo-deoxy-uridine (hereinafter referred to as IDU) which has astructural formula as shown in the following.

ironic O H 11 H l/ More particularly, it relates to production of-iododeoxy-uridine by the following process steps: 2'-deoxyuridine inacid or in water is uniformly mixed with a water-soluble organic solventcontaining thereiniodine; then a cation-exchange resin is added to themixture, thereafter the whole batch is heated in hot water bath at atemperature range of from 85C to 100C for 30 minutes under a refluxcondenser; and upon completion of heating, the resin is separated fromthe solution by filtration and the filtered solution is evaporated invacuo to crystallize the lDU.

Preparation of [DU has already been described in Biochimica etBiophysica Acta, Vol. 32, page 295 1959). According to this known art,lDU is obtainable by iodizing 2'-deoxy-uridine with iodine by use ofchloroform containing therein 1 normal nitric acid or 3 normal causticsoda as a solvent. 1n either case, however,

the rate of yield of the intended product can not exceed 56% which isnot favorable for industrialized production of lDU.

There has also been known another method of producing lDU, according towhich 2'-deoxy-uridine is iodized by either halogenated iodine or acomplexsalt of iodine monochloride and ammonium chloride or alkalichloride, which is represented by a general formula of: MC1.1Cl (where Mdenotes ammonium group or alkali metal), in hydrochloric acid oraliphatic low class alcohol heated to a temperature of 80C. This methodis better than the abovementioned methodin respect of the rate of yield,but it is still as low as 83 to 84%.

1t is therefore the primary object of the present invention to providean improved method of producing IDU at a higher rate of yield.

According to the present invention, there is provided a process forpreparation of 5-iodo-deoxy-uridine which comprises reacting the acidicsolution of 2- deoxy-uridine in a water soluble organic solventcontaining iodine with a cation-exchange-resins under heating.

The details of the present invention will be described hereinbelow withreference to preferred examples thereof.

The present inventors have conducted repeated experiments and studiesfor a simplified process step to obtain IDU at a higher rate of yieldthan that by the known methods, as the result of which they have foundthat, when 2'-deoxy-uridine is dissolved in' acid or wa- 2 heated, whileagitating the same, 2'-deoxy-uridine is completely iodized and therequired IDU can be obtained at a remarkable rate of yield of as high as93 to 95%. I

The acid to be used for dissolving 2'-deoxy-uridine in the first stepmay be any inorganic strong acid having a pH value of less than 2 (or0.01 to 2 normal) in solution. Example of most commonly used inorganicacid for the purpose of the present invention is: nitric acid, sulfuricacid, and hydrochloric acid.

The organic solvents to be used for dissolving iodine in theabovementioned second step may be any one of the following: alcohols,dioxane, chloroform, etc., the concentration of which ranges from 20 to80%.

The strong acidic cation exchange resins to be used in the third stepare limited to those having SO l-l or -COOH as the exchange group. Theyare: Diaion KBK, Diaion SK 1, Diaion SK 102, Diaion SK 1A, Diaion SK110, Diaion PK 204 to PK 228,v Zeollex SA, Amberlite IR 112, Amberlite120, Amberlite IR 122, Dawex 30, Dawex 50, Dawex X1, Dawex 50x26,Nalcite HCR, Nalcite HPR, Permutite Q, Permutite QX, Duolite C-l,Duolite-3, Duolite C-10, Duolite C -20, Duolite C-25, Duolite C-26, andso forth.

The relative amount of iodine to be mixed with 2- deoxy-uridine ispreferably more than twice as much as the mo] ratio of 2'-deoxy-uridine.Also, the relative amount of the cation exchange resin with respect to2- deoxy-uridine should preferably be an equivalent amount to that of2-deoxy-uridine. Further, the relative amount of the cation exchangeresin with respect to the mixture solution of 2'-deoxy-uridine andiodine is from 1 to 5% by weight perthe mixture solution.

The reaction mechanism of the cation exchange resin and 2'-deoxy-uridinehas yet tobe clarified, but, from the researches made so far, it can beinferred that a factor constituting double reaction caused in thereaction systemis adsorbed to the cation exchange resin.

The [DU thus obtained possesses excellent anti-virus action, hence itcan be used as an efficacious medicine for treatment of corneitis, etc.caused by herpes corneae. simplex" virus. I

In order to enable skilled persons in the art to reduce the presentinvention into practice, the following preferred examples are given. ltshould, however, be noted that the invention is not limited to theseembodiments alone, but any change may be made within the ambit ter, thenan iodine solution prepared by dissolving the same in an organic solventis added to the 2'-deoxyuridine solution and agitated, and subsequentlya catof the present invention as afforded by the appended claims.

EXAMPLE 1 l Gr of 2'-deoxy-uridine was dissolved in 10 ml of 0.5N-nitric acid (HNO to which 50 ml of dioxane solution containing therein2.25 gr of iodine (1 was added, and sufficiently agitated. Then, 2.5 mlof Diaion PK 216 (cation exchange resin) was added to the mixturesolution, and the whole batch was reacted for 30 minutes in a bath ofboiling'water, while agitating. Upon completion of the reactionunderheat, thecation exchange resin was removed from the solution byfiltration, and the filtrate was evaporated in vacuo to crystallize theIDU. As the result, 1.49 gr of IDU was produced at a rate of yield ofEXAMPLE 2 1 Gr of 2'-deoxy-uridine was dissolved in 10 ml of 0.5N-nitric acid (HNOg). to which 50 ml of chloroform solution containingtherein 2.25 gr of iodine (1:) was added and sufficiently agitated.Subsequently, 2.5 ml of Amberlite lR l20 was added to the mixturesolution, and the whole batch was reacted for 30 minutes in a bath ofboiling water, while agitating. After heating, the reacted solution wastreated and refined in the same manner as in Example 1 above, whereby1.46 gr of the [DU was obtained at a rate of yield of 93%.

EXAMPLE '3 l Gr of 2-deoxy-uridine was dissolved in i ml of 0.5 N-nitricacid (HNO to which 50 ml of ethanol solution containing therein 2.25 grof iodine (l was added and sufficiently agitated. Thereafter, 2.5 ml ofDawex 30 added to the mixture solution, and the whole batch was reactedfor 30 minutes in a hot water bath at 85C, while agitating. After theheating reaction, the reacted solution was treated and refined in thesame manner as in Example l above, whereby 1.51 gr of the IDU wasobtained at a rate of yield of 96%.

EXAMPLE 4 We claim:

1. A process for producing S-iodo-deoxy-uridine which consistsessentially of admixing a solution of 2'- deoxy-uridine in water or amineral acid selected from the group consisting of nitric acid, sulfuricacid and hydrochloric acid with a solution of iodine in a water solubleorganic solvent, heating the resultant mixture at a temperature of fromto l 10C in the presence of a strong acidic cation exchange resin in anamount of from 1 to 5% by weight, based on the weight of said mixture,while agitating said mixture, thereby iodizing said 2'-deoxy-uridine.

2. The process as claimed in claim 1, wherein said water soluble organicsolvent is selected from the group consisting of alcohols, dioxane, andchloroform.

3. The process as claimed in claim 1, wherein said cation exchange resinis selected from the group consisting of Diaion SK 1, Diaion SK 102,Diaion SK 1A, Diaion SK lit), Diaion PK 204 to PK 228, Zeollex-SA,Amberlite IR 112, Amberlite lR l20, Amberlite IR 122, Dawex 50, Dawex50x1, Nalcite HCR, Nalcite HPR, Permutite Q, Permutite QX, Duolite C-3,Duolite C-lO, Duolite C-20, Duolite C-25, and Duolite C-26.

4. The process as claimed in claim l,'in which 2- deoxy-uridine isdissolved in the acid or water in a relative amount of twice as much asthe molratio'of 2'- to 2-deoxy-uridine is equivalent to2'-deoxy-uridine.

1. A PROCESS FOR PRODUCING 5-IODO-DEOXY-URIDINE WHICH CONSISTSESSENTIALLY OF ADMIXING A SOLUTION OF 2''-DEOXY-URIDINE IN WATER OR AMINERAL ACID SELECTED FROM THE GROUP CONSISTING OF NITRIC ACID, SULFURICACID AND HYDROCHLORIC ACID WITH A SOLUTION OF IODINE IN A WATER SOLUBLEORGANIC SOLVENT, HEATING THE RESULTANT MIXTURE AT A TEMPERATURE OF FROM85* TO 110*C IN THE PRESENCE OF A STRONG ACIDIC CATION EXCHANGE RESIN INAN AMOUNT OF FROM 1 TO 5% BY WEIGHT, BASED ON THE WEIGHT OF SAIDMIXTURE, WHILE AGITATING SAID MIXTURE, THEREBY IODIZING SAID2''DEOXY-URIDINE.
 2. The process as claimed in claim 1, wherein saidwater soluble organic solvent is selected from the group consisting ofalcohols, dioxane, and chloroform.
 3. The process as claimed in claim 1,wherein said cation exchange resin is selected from the group consistingof Diaion SK 1, Diaion SK 102, Diaion SK 1A, Diaion SK 110, Diaion PK204 to PK 228, Zeollex-SA, Amberlite IR 112, Amberlite IR 120, AmberliteIR 122, Dawex 50, Dawex 50 X 1, Nalcite HCR, Nalcite HPR, Permutite Q,Permutite QX, Duolite C-3, Duolite C-10, Duolite C-20, Duolite C-25, andDuolite C-26.
 4. The process as claimed in claim 1, in which2''-deoxy-uridine is dissolved in the acid or water in a relative amountof twice as much as the mol ratio of 2''-deoxy-uridine.
 5. The processas claimed in claim 1, in which the relative amount of the cationexchange resin with respect to 2''-deoxy-uridine is equivalent to2''-deoxy-uridine.